Piperazine derivatives



PIPERAZINE DERIVATIVES Charles F. Geschiekter, Lorton, Va., Ebenezer E.Reid, Baltimore, Md., and John S. Pierce and Ying Ho Chen, Richmond,Va., assignors to The Geschickter Fund for Medical Research, Inc.,Washington, D.C., a corporation of New York States Patent No Drawing.Filed Oct. 5, 1959, Ser. No. 844,172 6 Claims. (Cl. 260-268) Thisinvention relates to derivatives of piperazine and this application is acontinuation-in-part of our co-pending application, Serial No. 670,654,filed July 9, 1957, now abandoned. More specifically, this inventionrelates to compounds of the following structure, herein identiand theirnon-toxic acid addition salts, Where each of A and A is a member chosenfrom the group consisting of H and CH and each of B and B' is a memberchosen from the group made up of pyrrolidino, piperidino, 2- methylpiperidino, 2,4-dimethy1-piperidino, morpholino and a dialkylaminoradical of the structure where each of R and R is an alkyl radicalcontaining from one to four carbons. In the individual compound C, A andA may be the same or may be dilierent; B and B may be the same or may bedifferent; R and R may be the same or may be different.

The compounds of structure C are pharmacologically active and are usefulin medicine. dilators and are useful in the control of asthma. They haverelatively low toxicities.

They are bronchial Also, the compounds of structure C are usefulintermediates for the formation of useful methiodies of the structure A(EH-CH2 B-CHzCHOHCHzN CHzCH NCHrCHOHCHrB-(CHsD These dimethiodides arerelaxants of voluntary musculature and can be used to replace curarewhere muscular relaxation is important.

In the present invention, compounds of structure C were prepared by oneof the following general reactions:

3,037,983 Patented June 5, 1962 equivalent. In reactions III and IV, Band B may be equivalent or may be different.

tion of compound C, given just above and it also includes the compoundC, itself, within the definitions of A, A, B and B, preparation. 7 V

The following reactions were used in the preparation of some of theintermediates used in the present specification:

l /CHCH2 /O\ NaOH H-N NH+2ClCHzCHCH:

CHzCH CHI-CH2 CHzCH (IE-CH2 /O\ NaOH HCON N-H+CICH:CHCH2 A OHzCHThisinvention includes the four methods of prepara-' given above,regardless of the method of CHrCH The intermediate formed in reaction 1above is used in reaction II in the preparation of compound C.'I'hefinal product in reaction 4 is used for the synthesis of C by thegeneral reaction IV. It is noted'in this latter reaction that B and Bmaybe equivalent or they may be difierent. The final product in reaction5 is used for the synthesis of C by reaction III. vAlso, in this case Cmay contain groups B and B which are equivalent or which are different;a 1

In the preparation of compounds of the structure 011-0112 B-CHCHOHCH2-NN-CH CHOHCH B omen as comprehended by above-identified structure C, thefollowing distilled epihydrinamines were used:

orncnezNouzcnoui (cmomcmonomomorr-iorr,

Also, crude 3-pyrrolidino-l,Z-epoxypropane of the structure 7 indicatethat in certain syntheses side reactions were decreased by carrying outthe reaction of the epihydrinamine and secondary amine in the presenceof a small amount of aqueous alkali.

In a typical reaction, to a solution of piperazine in ethanol was addedslowly two molar quantities of epihydrinamine. The reaction mixture,after standing for seveial hours at room temperature, was heated forseveral hours to approximately C. (Note: All temperatures in thisspecification are on the centigrade scale.)

The preferred method for the synthesis of compounds 7 of the structureis illustrated by reaction IV. a The same epihydrinarnines which servefor reaction I also serve for reaction IV.

Usually, in the purification of a compound of structure C, the reactionproduct was dissolved in aqueous hydrochloric acid and the compound Cwas precipitated as an oil, with alkali. All of the compounds of thisstructure reported in this specification were purified by vacuumdistillation. The boiling points given in the specification are for thepurpose of identification only and are not intended to limit the claims.

including quaternization of one or both of the tertiary amino groups inD. The compounds of structure D usstructure in this specification,obtained by distillation, is ually were so reactive that they underwentself-condenlikely a mixture of diastereoisomers. Each of the comsationon standing for a short time at room temperature pounds of structure Creported in Table I, with a few or even in the refrigerator. Due to thisactivity, the bi exceptions, is a liquid, usually rather viscous, or alowsepoxides of structure D usually were used for reaction meltingsolid. In general, the compounds of structure II, a bove, very soonafter their preparation.

C derived from trans-2,5-dimethylpiperazine melt higher Of the fourbisepoxides of structure D, only one, namely than the correspondingcompounds derived from pipera- Since each of the compounds of structureC contains at least two asymmetric carbons, each product of this zine,2-methyl piperazine or cis-2,5-dimethylpiperazine.

A partial separation of diastereoisomers of one of the 0 OH-CH2 0compounds of structure C is here described. A sample L of distilled1,4-bis[3-(di-n-butylamino)-2-hydroxypropyl] t H H piperazine of thestructure Tans 0 8 CHZCH: (CHHCHQCHZCHZ)2NCH2CHOHCHPN NCH2CHOHOH2N(GHEOHBCHZCH3)? CHgCH which gave an excellent analysis fornitrogen, remained an oil until it was seeded with a crystalline productof tained-as gums or viscous oils.

the same compound from another run. After standing The followingexamples are given to illustrate specific for a few hours the massbecame semi-solid. After methods which have been used in the synthesisof comstanding for about a month the sample was subjected pounds of thepresent invention but are not meant to limit to suction filtration. thescope thereof.

The residue in the Buchner funnel was placed on a clay plate to removeas much as possible of the liquid diastereoisomer. After standing on theclay plate for about three days the white solid melted at 5455. The

was isolated as a solid. The other bisepoxides were ob- EXAMPLE 11,4Bis[3- (Di-n-Propylamino)-2-Hydroxypropyl] Cis-ZJ-Dim'ethylpiperazineCH3 HEP-CH2 N-CH2CHOHCH2N(CH2CH2CH3)2 (E) as.

(CH3CHsCH2)zNCHgCHOHCHzcis filtrate in the suction flask became quiteviscous when cooled to about -10 but did not become a solid.

The original distillate, the solid and the filtrate gave nitrogenanalyses as follows:

Calculated for C H N O Nitrogen, 12.27%.

Nitrogen found, percent To 190 g. (1.20 mole) of3-di-n-propylamino)-1,2- epoxypropane was added slowly over a period ofone hour 68 g. (0.60 mole) of cis-2,idi-methylpiperazine dissolved in100 ml. of ethanol, the temperature being kept below 15 The reactionmixture was allowed to stand over night at room temperature and washeated on a gently boiling water bath for about 15 hours.

Original distillate 12.27 The mixture was cooled and was treated with1.5 1. of Solid (M.P. 54-55") 12. 1 N hydrochloric acid and with 500 ml.of ether. After Filtrate 12.09 separation, the aqueous layer was madestrongly basic. An oil came to the surface. The oil and a ueous la eTypical compounds of structure C of the present 1nq y r vention wereconverted into acid addition salts which were extracied Wlth 500 i l onePomon the such acids as hydrobromic acid, sulfuric acid, phosphoricelher solutlqn on evaporatlqn m an open .contamer acid, acetic acid,lactic acid, citric acid and thiodisalicy- 55 Welded a f l Y i the lieacid. Each of the first six acids listed above was found elher andYacuum d'lstluimon of the resldue yleided i' to form a soluble salt withabout twenty-five of the amino bls [3 d1 f Pr OP ylammo)'2"hydroxyp mpY1] a1 01S of Structure C methylprperazrne, 199-202 at 0.20 mm.

In the preparation of a typical compound of the fol- At tunes It flmnd lproducts j l lowing structure herein identified ture C whrch weresemi-solrds originally, on distillation yielded liquids which tended toremain in the liquid state,

some remaining in this form for several months or longer. 0 CHOHc v Somesamples, on being seeded, readily deposited crys- CE/ITLCHOHPN tals,some becoming solid in'appearance.

Compound E has been used efiectrvely clrmcally, 1n the CH2 |3H controlof asthma, in over one hundred cases. The dosage usually is 50 mg. Thiscompound is given orally, as the free base, dissolved in sesame oil andin a capsule or as the hydrochloride, dissolved in water. Also, it isgiven epichlorohydrin was caused to react with the piperazine,

H-CH; by intramuscular injection as the hydrochloride, in sterileaqueous solution.

\ The acute toxicity of the compounds of structure C of 23 the presentspecification, when tested in the rat, usually is between LD 50:100 mg./kg. and LD50==300 mg./kg. and the reaction product was treated withalkali. Us The acute toxicity of compound E in the rat is LD ually, theyields were low, likely due to side reactions, 50:400 mg./kg.

x to the surface.

The acute toxicities in the rat of a few compounds very closely relatedin structure to E are given below:

8 amino-Z-hydroxypropyl] cis-2,5-dimethylpiperazine, B.P. 184186 at 0.55mm.

CH3 LL 50 OlEl-CH2 MgJKg.

(CH3CHzCH2)zNCHzCHOHCHzN N-CH2CHOHCHzN(CHzCHzGHs)2 250 trans CHQOH CH3CHCH2 (CHaCHzGHzhNCHzCHOHCHzN N-CH2CHOHCHzN(CHzCHzCHa)2 300 CH CH CH3OHGH2 (CH3OH2CH2CH2)2NCH2CHOHCH2N TOHZCHOHCH2N CH2CH2OH2OH3 Z 200 (isCE2C-H CH3 CHI-CH;

(cnaornonlcrmmomononoum C 2CE2 Each of the four compounds above, as wellas compound E, has been used to relax muscle spasm in arthritics, insprained backs and for muscular spasm in thegastronongouononzmonzougcmcnm 275 EXAMPLE 3 1 ,4-Bis [3-(2,4-Dzmethylpiperidino) -2-Hydr0xypropyl] T runs-2,5-Dimethylpiperazine intestinal tract. The results were good. Each ofthese four compounds proved effective in relieving asthma.

EXAMPLE 2 1,4-Bis [3-(Diethylamino)-2-Hydr0xypr0pyl] Cis-2,5-Dimethylpiperazine CH: DH-CH2 (GH3CH2)2NCH2CH OHGHzN V CHaCH CH3 cis Amixture of 25.8 g. (0.20 mole) of 3-diethylamino-' 1,2-epoirypropane.12.8 g. (0.10 mole) of cis-ZJ-Gimethylpiperazine in 20 ml. of ethanoland '8 drops of waterwas allowed to stand over night at room temperatureand was heated to 50 for 7 hours, On treatment-with 500 m1. of water the"reaction mixture tended 'to stay in solution.

On addition of 50 g. of potassium carbonate an oil came vacuumevaporated. Onsecond distillation the residue The oil was extracted 150m1. of 1 ether. The ether layer was filtered and theether was t Amixture of 20.3 g. of 3-( 2,4-dimethylpiperidino) -1,2-

' epoxypropane, 8.0 g. of trans-2,5-dimethyl-piperazine in 30 ml. ofethanol and 4 drops of Water was allowed to stand at room temperaturefor two days. The reaction mixture was warmed on the water bath forabout 20 hours.

On treatment of the reaction mixture with 1 liter of water, an oil,mixed with solid, rose to the surface. The p 60 lower aqueous layer wasdiscarded. The upper layer was treated' with 400 ml. of ether and 1liter of water. The aqueous layer was discarded. The upper ether layerand some undissolved solid was vacuum-evaporated to remove the ether andthe residue was vacuum-distilled. The

. yield of 1,'4-bis [3-(2,4-dimethylpipe1idino)-2-hydroxypropyl]trans-2,5- dimethylpiperazine, B.P. 212-213 at .10 0 mm was 11 gEXAMPLE4 1,4-Bis [3-,(Di-n-Butylamino)-2-Hydr0xypr0pyl] Piperazine 9 Amixture of 38.8 g. (0.20 mole) of piperazine hexaand epihydrinamiues ofthe structure hydrate in ml. of alcohol and 74.4 g. (0.40 mole) of3-(di-n-butylamino)-l,2-epoxypropane, after standing for several hours,was heated to 60 for 7 hours. The re- BOH2OHOH:

action mixture was treated with 1.5 l. of water and 500 ml. of ether.The ether solution was washed with 1 l. in ethanol solution and in thepresence of a small amount of water. Since much of the ether was lost,at this point of aqueous sodium hydroxide solution, were allowed to 200ml. of ether was added. The ether solution was stand at roomtemperature, usually over night, and then; evaporated and the residuewas vacuum-distilled. On the were heated gently for about four to sixhours, sometimes second distillation the yield of 1,4-bis [3-(di-n-butyl10 longer.

amino)-2-hydroxypropyl] piperazine, B.P. 225228 at The reaction mixturewas treated with water or water 0.50 mm. was 32 g. (35% of theory). andalkali and the oil which came to the surface was separated, frequentlyby ether-extraction. The oil was EXAMPLE 5 subjected to fractionaldistillation in a vacuum. 1,4-Bis[3-(Ethylbutylamino)-2-Hydr0xypr0pyl]-2- 15 In some runs a slight excessof substituted piperazine Methylpiperazine was used; in some runs thereverse was true.

CH3 CHaCHz /CH-CH2 CHzCHa NCH2CHOHCHz-N NCHzCHOHCH2-N 11-43-1119 CHzOH:11-04119) I A mixture of 10 g. (0.10 mole) of Z-methylpiperazine EXAMPLE7 in ml. of ethanol and 32 g. (0.20 mole) of 3-(ethylbutylamino)-l,2-epoxypropane, after standing for a short P y yp py Ytime, was heated to 60 for 4 hours. The product wasamin0)-2-Hydr0xypr0pyl] Cz's-Z,S-Dimethylpiperazine (3H3 OH GH- V(JR-0H2 O N-CHzCHOHCH -N N-OHZOHOHCHZN(CH2OH2CH2CH3)B CH2CH2 ClS CHZCHtreated with 400 ml. of water. An oily upper layer was To a solution of7.5 g. (0.04 mole) of 3-(di-n-butylformed when 50 g. of potassiumcarbonate was added. amino) -1,2-epoxypropane in 10 ml. of ethanol wasadded The oily layer was separated, dissolved in ether and the 40 2drops of 6 N sodium hydroxide solution and 10 g. ether solution wasfiltered. On vacuum-evaporation of (0.04 mole) of1-(3-morpho1ino-2-hydroxypropyl)cis-2,5 the ether andvacuum-distillation of the residue, the yield dimethylpiperazine in 10ml. of ethanol. The mixture of 1,4-bis[3-(ethylbutylamino)-2-hydroxypropyl]-2- was allowed to stand for 2 daysand was heated just below methylpiperazine, B.P. l99202 at 0.30 mm., was21.1 boiling for about 4 hours. g. (51% of theory). To the reactionmixture was added 125 ml. of water. Some oil separated. The amount ofoil was increased EXAMPLE 6 by treatment with 125 ml. of 6 N sodiumhydroxide solution. The oil was extracted with 100 ml. of ether. TheGeneral Merhod for Preparation of Compounds of the ether was evaporatedand the residue was vacuum-dis- Structure tilled. The yield of1-[3-(morpholino)-2-hydroxypropyl]-4-[3-(dibutylamino)-2-hydroxypropyl1cis 2,5 dimethyl- 7 piperazine, B.P.2l3-214 at 0.09 mm., was 7.0 g. (39 OHOH2 per-cent of theory).B-crnorroHomN N-CHzCHOHCHrB' EXAMPLE 8 2? 1 -(3-Piperidino-Hyd'roxypropyl -4 (3 -D iethylamino-Z-Hydroxypropyl)-2-Methylpiperazine 0H3 onion. (EH-CH2 CH2 N-CH2OHOHCH2 NNCH2CH0HCHzN(O2Hs)n OI-TECH; CHZCEz Approximately equimolar quantitiesof substituted pi- To a solution of 2.58 g. (0.020 mole) of 3-diethy1-perazines of the Stru t e amino-1,2-epoxypropane in 25 ml. of ethanolwas added 4 5 ml. of 6 N sodium hydroxide solution and 6.2 g. 0.027mole) of 1-(3-piperidino-Z-hydroxypropyl)-2-methylpi- B-CHqCHOHCHz-N NHperazine in 25 ml. of ethanol. After standing for a few OHQCH days atroom temperature the reaction mixture was heated just below boiling forabout 6 hours.

11 .01: treatment of the reaction mixture with 300 m1. of 6 N sodiumhydroxide solution an oil separated. This oil was extracted with 100 ofether. The ether layer,

on vacuum-evaporation and vacuum distillation of the residue, yielded2.4 g. (32% of theory) of 1-(3-piperidino 2 hydroxypropyl) 4 (3diethylamino 2 hydroxypropyl) -4-( 3-diethylamino-Z-hydroxypropyl-2-methylpiperazine, B.P. l90l91 at 0.15mm.

Note: Likely some isomeric 1-(3-diethylamino-2-hydroxypropyl) -4- 3-piperid ino-2-hydroxypropyl) -2-methy1- 1 piperazine was present, also.

EXAMPLE 9 1 [3 -M orpholino-Z-Hy'droxypropyl -4 [3-( 2,4 -Dimethyl-.

piperia'ino) -2-Hyd'roxypropyl1Piperazin e 1 2 EXAMPLE 10 1-(3-Dimethylamino-2-Hydroxypropyl)-4 (3-M0rpholin0- Z-Hydroxypropy-l Cz's-2,5 -Dimethylpiperazine CH H-CHQ OHzCHa (CHalnNCHzGHOHOHz-NCH2CHOHCH2N O cis omen onion,

To 5.16 ml. (0.06 mole) of epichlorohydrin in ml. of ethanol was added 1ml. of 2 N sodium hydroxide solution. To this mixture was added slowlywith stirring over a period of 1.5 hours a solution of 12.9 g. (0.053mole) of 1-(3-morpholino-2-hydroxy-propyl)cis-2,5-dimethylpi' perazine,the temperature being kept below After 3 hours of stirringthe reactionmixture was treated with a V OHs CHzCH: CHzCHa EH-CH O N-CHQGHOHCH2N.N-CH2CHOHCH2N CHCHs CHQG a CHgCHz CHzCHz 1 was allowed to stand forabout two days and was heated just below boiling for about 4 hours.

The reaction mixture was treated 250 ml. of 3 N sodium hydroxidesolution. The oil, which separated, was dissolved in ether and wasfiltered. On vacuumevaporation of the ether and vacuum-distillation ofthe residue there was obtained 4.5 g. (40% of theory) of I-(B-morpholino2 hydroxypropyl)-4-[3-(2.4dirnethylpiperidino) -2-'hydroxypropyl]piperazine, B.P. ZZZ-223 at 0.10mm.

solution.

solution of 4 g. of sodium hydroxide dissolved in 60 ml. of water. After1 hour of stirring the mixture was extracted with 150 ml. of ether. Tothe ether solution was added 0.10 mole of dimethylamine in 25 percentaqueous The mixture was allowed to stand over night. The ether wasvacuum-evaporated and the residue remaining was heated gently on a sandbath for about 4 hours.

The reaction mixture was treated with 125 ml. of 6 N sodium hydroxidesolution. An oily layer was formed.

On addition of 125 ml. of'water much of this oil dissolved. The amountof oily layer was increased by the addition of another 125 ml. portionof 6 N sodium hydroxide solution. The oil was extracted with 125 ml. ofether. On vacuum-evaporation of the ether and vacuum- 40 distillation,ofthe residue there was obtained 1.8 g. (10

propyl) 4 (3 morpholino 2-hydroxypropyl)cis-2,5-dipercent of theory) ofV 1-(B-dimethylamino-Z-hydroxyj methylpiperazine, B.P. 194-196? at 0.09mm. pressure.

In Table I are given representative compounds of struc- The examplegiven just below illustrates reactions 5 C in which A, A" B and arevaried.

and III. 1

Q TABLE I V V CH-OH= BCH1OHOHCHN N-CHzCHOHCHr-B omo A A B B B.P.O. PressMolecular Nitrogen, Percent (uncon) mm. formula caled. found H rr ormgNwort 21m. -150 0.15 oinmlNioi' 15.01 15.01

H p N N V. 198-204 V 0.07 cliHnNloi 16.48 10.40

, V 7 V w V 1 n N V V 210-215 V 0.30 o omuNioa 15.20 15.00

grrj H ,N (nC4H0)z- 7 211-214 0.10 021111501101 13.01 15.70

H s L wreat 220-221 0.15 011731101103 13.52 13. 52 1 e 1; H N: oH=220-223- 0.10 C11H11N10= 14.08 13.03

; VCH:

H 'H 220-221 0.50 CuHhNiOa 1115 13.03

A A B B B.P. 0. Press. Molecular Nitrogen, Percent (uncon) mm. formulacalcd. found (6h CH3 CH3 CH3 H d N .0 Hz 227-234 0. 150. 20 CzaHszNtOa12.28 12.00

CH3 CH3 (n-C 3H7) 2N N (nCsH?) 2 198-202 0. 20 C24H52N402 13. 04 13.

CH3 CH9, H3O N N(DC4Hu)z 223-229 0. 07 C27H55N40fl 11. 98 12.

CH3 CH3 (ll-43411 N N (ll-C4110): 221-222 0. 45 C28H6BN40fl 11. 56 11.54

- Trans. b cis.

kanolamines of structure C with three molar quantities V of methyliodide at room temperature for approximately three weeks. Details aregiven below for the formation and isolation of a typical dimethiodide.

. EXAMPLE 11 Reaction of1,4-Bis[3-(2-Methylpiperidin0)-2-Hydr0xypropyl]Cis-2,5-Dimethylpiperazinewith Methyl Iodide A solution of 4.3 g. (0.01 mole) of the titlealkanolamine and 4.26 g. (0.03 mole) of methyl iodide in ap proximately25 ml. of ethanol was allowed to stand for about three weeks in astoppered flask. On the addition of anhydrous ether a gum was formed.After trituration of the gum with ether it was dissolved in absoluteethanol. Again the gum was precipitated by [the addition of anhydrousether. On trituration with ether the gum solidified. The solid wasfiltered and dried in a vacuum desiccator. The quaternary salt thusobtained was a high melting solid, very soluble in water but notappreciably hygroscopic. Calculated for (C H N O (CH I) I, 36.0%. Found,36.1%.

By the same general procedure, dimethiodides were obtained 'by thereaction of methyl iodide onl,4-'bis(3-din-propylarnino-Z-hydroxypropyl)cis-2,5 dimethylpiperazine,1,4 bis [3 Z-methylpiperidino) -2-hydroxypropyl] 2-methylpiperazine and1,4 bis[3-(2,4-dimethylpiperidino)-2=hydroxypropyl]cis-2,5-dimethylpiperazine.of these products had high melting points and were very (CHsCHzCHr)zNCHgCHOHCHr-N (GHzOHzOHQ NCHzOHOHOHzN cis eis

trans soluble in water. being hygroscopic.

The dimethiodides of compounds of structure C are curare-like substanceswhich have proved capable of complete relaxation of skeletal musculaturewithout the production of respiratory paralysis. These compounds havethe advantage over many curare-like products that they are potent buttransient in action.

We claim:

1. A compound selected from the group consisting of They were on theborder line as to CHa (DH-CH2 NCH:CHOHCH2N(CHgCH CHa):

.CHzCH 3. A compound of the formula CH: )HCH2 V N-GHzGHOHCHzN(CHCHzCHs):

' CHQCH H: '4. A compound of the formula (IJHCH2N-OI-IQQHofloHtNwHrcnzomom CHrCH- 5. A compound of the formula CH3 )HCHn(OHgCHgCHqCHahNCHzCHOHCH N N-OHaCHOHCfl NwHzOHqCHaCHm 01530 1 6. Acompound of the formula CH3CH2 N0H20HoHcmmomcmomom)1 CHQCHZ Noreferences cited.

(CHsCHzCHgCHz) NOHQCHOHCHZN UNITED STATES PATENT OFFICE CERTIFICATE OFCORRECTION Patent No. 3,037,983 June 5, 1962 Charles F. Geschickter eta1.

It in hereby certified that error eppeere in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column l line 46, for "methiodies" read methiodides column 2, line 3,for

CH2CHCH read CH CHCH same column 2, line 69 and column 3, lines 4, l0,l7, and 24, for I A if cu-cu H-CH Hco' t y read. HCON i y cH cH CH CHcolumn 3, line 4, for

CH C EH readv CH CQ EH line 24, strike out line 37, for

ClCH O CH read ClCH CHCH column 5 line 60,strike out the period andinsert instead a comma; column 6, line l2, for

N-CHQ CH read NCH CHCH column 6, line 41, for "3-di-n-propy1amino) readPatent No. 3,037,983

3 (din-propy1amino) column 8, line 6, for "LL 50" read LD 50 column 11,line 7, strike out "-4-(3- diethylamino-2-hydroxypropy1"; column 12,line 41, strike out "propy1)-4(3-morpholino2hydroxypropyl)cis-2,5di" andinsert the same after "hydroxy-" in line 42, same column 12; column 13,TABLE 1, line 1, for

H read 1-1 same line 1, for

H CH

read

column 13, line 9, for

6 read i both occurrences; same column 13, line 12, for

5 read H column 15, line 1, for

CH H

read

Patent No. 3,037,983

;ame line I for H read H :ame column 15, line 3, for

3 read 3 (SEAL) kttest: ERNEST W. SWIDER attesting Officer DAVID L. LADDCommissioner of Patents

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THEFROMULA